Preeclampsia is more common in obese women. In our population the risk is 3 times greater than that of lean women. The frequency of obesity (25-30%) results in an attributable risk for preeclampsia of 35 to 50%. This increased risk is not only for mild but also for severe and early onset preeclampsia. This frequency of obesity is similar in developed countries and obesity is becoming more common in developing counties. It is important to understand the mechanism(s) by which obesity increases the risk of preeclampsia. A key question: what factor(s) contribute or cause a particular obese woman to develop preeclampsia? We will ask whether percent body fat, or distribution or accrual of fat, are related to preeclampsia. We will also study metabolic and inflammatory changes, known to be present in both preeclampsia and obesity, testing the hypothesis that obese women who develop preeclampsia will manifest more abnormalities in these factors in early pregnancy. We will also test whether periconceptional diet, sleep disorders or smoking are different in obese women who develop preeclampsia. These questions will be tested primarily in a longitudinal study of 600 obese nulliparous women sampled at 8-10, 18-20, 34-36 weeks gestation and at delivery. Because severe preeclampsia is rare, we will examine the metabolic, inflammatory and angiogenic changes in a cross sectional study of 25 obese and 25 lean women, with or without severe preeclampsia. Our preliminary data suggest that asymmetric dimethylarginine (ADMA), the endogenous inhibitor of the interaction of L-arginine with nitric oxide synthase (NOS), is increased in early pregnancy in obese women who subsequently develop preeclampsia. All of the factors we are studying are known to increase ADMA and we will test whether these factors converge to increase ADMA with subsequent vascular dysfunction. We will test this by measuring and correlating ADMA with the other factors but also by administering L-arginine to 30 women between 16 and 19 weeks gestation, testing vascular dysfunction, metabolic and inflammatory markers before and after treatment in a doubly masked randomized controlled trial. The goal of Project II is to identify modifiable factors in obese women to prevent preeclampsia and to determine if there is a common target, overcoming the effect of ADMA to inhibit NOS that would be useful to prevent preeclampsia.